TWI771839B - Formulation comprising tetracyclic compounds in high dose - Google Patents

Abstract

The present invention provides relates to a composition or a formulation, wherein, the composition or the formulation is formed by granulating 9-ethyl-6,6-dimethyl-8-(4-morpholine -4-yl-piperidine-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or a salt thereof and making the obtained granules coexist with a disintegrant, to thereby enable the composition or the formulation containing the compound in high dose to have excellent eluting property.

Description

Formulations containing tetracyclic compounds in high doses

The present invention relates to a pharmaceutical composition of a tetracyclic compound having an ALK inhibitory action, particularly a preparation for oral administration and the like.

Anaplastic Lymphoma Kinase (ALK) is one of the receptor-type tyrosine kinases belonging to the insulin receptor family (Non-Patent Document 1, Non-Patent Document 2), and it has been reported that ALK gene abnormality can cause other tyrosine kinases. Generation of abnormal kinases from gene fusions.

Diseases associated with ALK abnormality, such as cancer and cancer metastasis (Non-Patent Document 1, Patent Document 1), depression, cognitive dysfunction (Non-Patent Document 2), etc. are known, and the provision of ALK inhibitors is to provide such diseases effective treatment and preventive medicine.

Compounds with an ALK inhibitory effect are known: compounds represented by formula (I) (compound name: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidine) pyridin-1-yl)-11-side oxy-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile) etc. (Patent Document 2, Patent Document 3, Patent Document 4).

The drug is preferably developed into a dosage form that can be administered orally, but whether it can be developed into a preparation for oral administration depends on the level of bioavailability of the drug. One of the factors affecting the bioavailability includes the water solubility of the drug. Generally speaking, the bioavailability of a poorly water-soluble or insoluble compound is low when it is orally administered. Improving bioavailability of active ingredients and improving oral absorbability are important for stably exerting the medicinal effects of active ingredients.

On the other hand, in order to increase the blood concentration of the drug of the poorly water-soluble or insoluble compound, and to enhance the therapeutic effect, it is conceivable to use the drug in a high dose. However, for the oral administration of the preparation, it is better to reduce the number of pills taken and the frequency of taking each time to improve the convenience of patients. Among them, it must be a preparation containing a high content of the drug per unit of preparation.

A composition in which a compound represented by formula (I) or a salt thereof and a dissolution aid coexist has been reported (Patent Document 4). In addition, it has been reported that for the purpose of improving the solubility and oral absorbability of poorly soluble substances, a composition obtained by wet granulation in the presence of water containing a poorly water-soluble component such as steroid, a surfactant, and an organic polymer ( Patent Document 5).

[Prior Art Literature]

[Patent Literature]

[Patent Document 1] JP2009100783 (A)

[Patent Document 2] Japanese Patent No. 4588121

[Patent Document 3] Japanese Patent No. 4918630

[Patent Document 4] Japanese Patent Laid-Open No. 2012-126711

[Patent Document 5] Japanese Patent Laid-Open No. 2008-280352

Non-patent literature

[Non-Patent Document 1] Nature, Vol. 448, pp. 561 to 566, 2007

[Non-Patent Document 2] Neuropsychopharmacology, Vol. 33, pp. 685 to 700, 2008

The inventors of the present invention found that during the dissolution process of a formulation containing the compound represented by formula (I) or its salt in a high amount, the compound or its salt aggregates and does not disintegrate, resulting in a decrease in dissolution properties. The inventors of the present invention, as a result of careful examination in order to solve this problem, found that by forming granules containing the compound represented by the formula (I) or a salt thereof that is poorly water-soluble or insoluble, and coexisting the granules with a disintegrating agent, it is possible to A preparation containing a high amount of the compound represented by the formula (I) or a salt thereof and having excellent dissolution properties is obtained.

In addition, the present inventors found that the production method of sodium lauryl sulfate, which is a surfactant, affects the dissolution properties of poorly water-soluble or insoluble compounds.

The inventors of the present invention, based on the above knowledge, made further studies and completed the this invention.

That is, the present invention is as follows.

(1-1) A pharmaceutical composition comprising (i) granules containing the compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(1-2) The composition according to the item (1-1), which contains 5% by weight or more of the above-mentioned (ii) disintegrant with respect to the entire composition.

(1-3) The composition according to the item (1-1) or (1-2), which contains 5 to 30 wt % of the disintegrant in (ii) above with respect to the entire composition.

(1-4) The composition according to any one of (1-1) to (1-3), which contains 7.5% by weight or more of the above-mentioned (ii) disintegrant with respect to the entire composition.

(1-5) The composition according to any one of (1-1) to (1-4), which contains the above-mentioned (ii) disintegrant in an amount of 7.5 wt % or more and 30 wt % with respect to the entire composition the following.

(1-6) The composition as described in any one of (1-1) to (1-5), wherein the aforementioned (ii) disintegrant is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxypropyl Cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, knot Crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(1-7) The composition according to any one of (1-1) to (1-6), wherein the aforementioned (ii) disintegrant is when the sixteenth disintegrant is added per 1.0 g of the disintegrant. In the second revision of the Japanese Pharmacopoeia dissolution test, the volume of the first solution is 20 mL, and the volume is more than 2.5 times the disintegrant.

(1-8) The composition according to any one of (1-1) to (1-6), wherein the (ii) disintegrant is selected from the group consisting of: low-substituted hydroxypropyl cellulose, carboxymethyl Cellulose calcium, sodium bicarbonate, and alpha starch.

(1-9) The composition according to any one of (1-1) to (1-8), wherein the (ii) disintegrant is calcium carboxymethylcellulose.

(1-10) The composition according to any one of (1-1) to (1-9), wherein the granules contain a disintegrant in the granules.

(1-11) The composition according to any one of (1-1) to (1-9), which contains (i) a compound represented by formula (I) or a salt thereof, and a disintegrant granules, and (ii) a disintegrant.

(1-12) The composition according to any one of (1-10) or (1-11), wherein the disintegrant contained in the granules is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxyl Propyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(1-13) The composition according to any one of (1-10) or (1-11), wherein the disintegrant contained in the granules is the amount of the disintegrant when the first 1.0 g of the disintegrant is added. Sixteen revisions of the Japanese Pharmacopoeia Dissolution Test The volume of the first solution is 2() mL, and the volume becomes more than 2.5 times the disintegrant.

(1-14) The composition according to any one of (1-10) to (1-13), wherein the disintegrant contained in the granules is selected from the group consisting of calcium carboxymethyl cellulose, low-substituted Hydroxypropyl cellulose, starch-sodium glycolate, and alpha starch.

(1-15) The composition according to any one of (1-10) to (1-14), wherein the disintegrant contained in the granules is calcium carboxymethylcellulose.

(1-16) The composition according to any one of (1-1) to (1-15), wherein the particles contain a dissolution aid in the particles.

(1-17) The composition according to any one of (1-1) to (1-15), which comprises (i) a compound represented by formula (I) or a salt thereof, a disintegrant, and granules of dissolution aids, and (ii) disintegrants.

(1-18) The composition as described in item (1-16) or (1-17), wherein the aforementioned dissolution aid is selected from the following group:

Citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyethylene (40) Stearate (polyoxyo 40 stearate), refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, methyl alcohol Aminoalkyl acrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone ( copolyvidone), cellulose acetate phthalate, tartaric acid, dioctyl sodium sulfosuccinate, corn gluten, skimmed milk powder, sorbitan trioleate, lactic acid, aluminum lactate, palmitic-ascorbic acid, hydroxyethyl Methyl Cellulose, Hydroxypropyl Methyl Cellulose Acetate Succinate, Polyoxyethylene Alkene (105) polyoxypropylene (5) diol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene 35 castor oil, poly(4-styrene sulfonate sodium), polyvinyl acetal diethylaminoacetic acid Ester, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauryl alcohol polyoxyethylene ether (lauromacrogol), sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate , vinylpyrrolidone-vinyl acetate copolymer, sodium lauryl sarcosinate, acetyl tryptophan acid, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, decyl sulfate Sodium, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate.

(1-19) The composition according to any one of (1-16) to (1-18), wherein the dissolution aid is sodium lauryl sulfate.

(1-20) The composition described in the item (1-19), wherein sodium lauryl sulfate is obtained by crystallization.

(1-21) The composition according to the item (1-19) or (1-20), wherein the sodium lauryl sulfate is NIKKOL SLS.

(1-22) The composition according to any one of (1-19) to (1-21), wherein sodium lauryl sulfate is a 1/8 hydrate crystal.

(1-23) The composition according to any one of (1-16) to (1-22), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 60.

(1-24) The composition according to any one of (1-16) to (1-23), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 30.

(1-25) The composition according to any one of (1-1) to (1-24), wherein The aforementioned granules contain a binder within the granules.

(1-26) The composition according to the item (1-25), wherein the binder is hydroxypropyl cellulose.

(1-27) The composition according to any one of (1-1) to (1-26), wherein the particles are obtained by wet granulation.

(1-28) The composition according to any one of (1-1) to (1-27), wherein the particles have an average particle diameter of 150 μm or more.

(1-29) The composition according to any one of (1-1) to (1-28), wherein the particles have an average particle diameter of 180 μm or more.

(1-30) The composition according to any one of (1-1) to (1-29), wherein the particles have an average particle diameter of 200 μm or more.

(1-31) The composition according to any one of (1-1) to (1-30), wherein the particles have an average particle diameter of 250 μm or more.

(1-32) The composition according to any one of (1-1) to (1-31), wherein the particles have an average particle diameter of 1 mm or less.

(1-33) The composition according to any one of (1-1) to (1-32), wherein the particles have a bulk density of 0.5 g/mL or more and a tap density of 0.6 g/mL or more.

(1-34) The composition according to any one of (1-1) to (1-33), which contains the compound represented by the formula (I) or the compound represented by the formula (I) when converted into a free drug relative to the entire composition. Salt 20 to 70% by weight.

(1-35) The composition according to any one of (1-1) to (1-34), wherein The compound represented by formula (I) or its salt is contained in 35 to 60 wt % in terms of free drug with respect to the entire composition.

(1-36) The composition according to any one of (1-1) to (1-35), wherein the compound represented by the formula (I) or a salt thereof is a compound represented by the formula (I) monohydrochloride.

(1-37) The composition as described in the item (1-36), wherein the monohydrochloride of the compound represented by the formula (I) is at 8.4°, 14.0°, 16.7° in the powder X-ray diffraction pattern Diffraction angles (2θ) around °, 18.8°, and 23.3° have peak crystals.

(1-38) A pharmaceutical preparation containing the composition described in any one of (1-1) to (1-37).

(1-39) The pharmaceutical preparation according to the item (1-38), which is a preparation for oral administration.

(1-40) The pharmaceutical preparation according to the item (1-39), wherein the preparation for oral administration is a solid preparation.

(1-41) The pharmaceutical preparation according to the item (1-40), wherein the solid preparation is a tablet, a capsule or a granule.

(1-42) A capsule filled with the composition described in any one of (1-1) to (1-37).

(1-43) The preparation according to any one of (1-38) to (1-42), wherein each unit of the preparation contains 60 mg to 240 mg of the compound represented by formula (I) or a salt thereof when converted into a free drug .

(1-44) The preparation as described in any one of (1-38) to (1-43), wherein each The unit preparation contains 140 mg to 190 mg of the compound represented by formula (I) or a salt thereof when converted into a free drug.

(2-1) A pharmaceutical preparation comprising (i) granules containing the compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(2-2) The preparation according to the item (2-1), which contains 5% by weight or more of the disintegrant in (ii) above with respect to the entire preparation.

(2-3) The preparation according to the item (2-1) or (2-2), which contains the above-mentioned (ii) disintegrant in an amount of 5 wt % or more and 30 wt % or less with respect to the entire preparation.

(2-4) The preparation according to the item (2-1) or (2-2), which contains 7.5% by weight or more of the disintegrant (ii) above with respect to the entire preparation.

(2-5) The preparation according to any one of (2-1) to (2-4), which contains the above-mentioned (ii) disintegrant in an amount of 7.5% by weight or more and 30% by weight or less with respect to the entire preparation.

(2-6) The preparation according to any one of (2-1) to (2-5), wherein the aforementioned (ii) disintegrant is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxypropyl cellulose carboxymethyl cellulose calcium, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(2-7) The preparation according to any one of (2-1) to (2-6), wherein the (ii) disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium bicarbonate, alpha starch.

(2-8) The preparation according to any one of (2-1) to (2-7), wherein the (ii) disintegrant is calcium carboxymethylcellulose.

(2-9) The preparation as described in any one of (2-1) to (2-8), wherein the aforementioned granules contain a disintegrant in the granules.

(2-10) The preparation according to any one of (2-1) to (2-9), comprising (i) a compound represented by formula (I) or a salt thereof, and a disintegrant Granules, and (ii) a disintegrant.

(2-11) The preparation according to the item (2-10), wherein the disintegrant contained in the granules is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose Calcium, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(2-12) The preparation according to any one of (2-9) to (2-11), wherein the disintegrant contained in the granules is selected from the group consisting of calcium carboxymethyl cellulose, low-substituted hydroxyl propylcellulose, and starch-sodium glycolate.

(2-13) The preparation according to any one of (2-9) to (2-12), wherein the disintegrant contained in the granules is calcium carboxymethyl cellulose.

(2-14) The formulation as described in any one of (2-1) to (2-13), wherein the aforementioned granules contain a dissolution aid in the granules.

(2-15) The preparation according to any one of (2-1) to (2-14), comprising (i) a compound represented by formula (I) or a salt thereof, a disintegrant, and Granules of dissolution aid, and (ii) disintegrant.

(2-16) The formulation as described in any one of (2-14) or (2-15), wherein the aforementioned dissolution aid is selected from the following group:

Citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyethylene (40) Stearic acid ester, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, aminoalkane methacrylate Ester copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, acetic acid phthalic acid Cellulose, tartaric acid, dioctyl sodium sulfosuccinate, corn gluten, skimmed milk powder, sorbitan trioleate, lactic acid, aluminum lactate, palmitic-ascorbic acid, hydroxyethylmethylcellulose, hydroxypropyl Methyl Cellulose Acetate Succinate, Polyoxyethylene (105) Polyoxypropylene (5) Diol, Polyoxyethylene Hydrogenated Castor Oil 60, Polyoxyethylene 35 Castor Oil, Sodium Poly(4-styrenesulfonate) ), polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauryl alcohol polyoxyethylene ether, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate , Sodium Dodecylbenzene Sulfonate, Vinylpyrrolidone-Vinyl Acetate Copolymer, Sodium Lauryl Sarcosinate, Acetyltryptophan, Sodium Methyl Sulfate, Sodium Ethyl Sulfate, Butyl Sulfate Sodium, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate.

(2-17) The preparation according to any one of (2-14) to (2-16), wherein the dissolution aid is sodium lauryl sulfate.

(2-18) The preparation according to the item (2-17), wherein sodium lauryl sulfate is obtained by crystallization.

(2-19) The preparation as described in item (2-17) or (2-18), wherein lauryl sulfur Sodium is the crystal of 1/8 hydrate.

(2-20) The preparation according to any one of (2-14) to (2-19), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100:60 .

(2-21) The preparation according to any one of (2-14) to (2-20), wherein the weight ratio of the compound represented by formula (I) to the dissolution aid is 100:2 to 100:30 .

(2-22) The preparation according to any one of (2-1) to (2-21), wherein the aforementioned granules are obtained by wet granulation.

(2-23) The preparation according to any one of (2-1) to (2-22), wherein the particles have an average particle diameter of 150 μm or more.

(2-24) The preparation according to any one of (2-1) to (2-23), wherein the particles have an average particle diameter of 180 μm or more.

(2-25) The preparation according to any one of (2-1) to (2-24), wherein the particles have an average particle diameter of 200 μm or more.

(2-26) The preparation according to any one of (2-1) to (2-25), wherein the particles have an average particle diameter of 250 μm or more.

(2-27) The preparation according to any one of (2-1) to (2-26), wherein the average particle diameter of the particles is 1 mm or less.

(2-28) The preparation according to any one of (2-1) to (2-27), wherein the particles have a bulk density of 0.5 g/mL or more and a tap density of 0.6 g/mL or more.

(2-29) The preparation according to any one of (2-1) to (2-28), wherein the compound represented by the formula (I) or a salt thereof is one of the compounds represented by the formula (I) hydrochloric acid Salt.

(2-30) The preparation according to the item (2-29), wherein the monohydrochloride salt of the compound represented by the formula (I) is at 8.4°, 14.0°, 16.7° in the powder X-ray diffraction pattern , 18.8°, 23.3° around the diffraction angle (2θ) has the crystal of the wave peak.

(2-31) The preparation according to any one of (2-1) to (2-30), which is a preparation for oral administration.

(2-32) The preparation according to the item (2-31), wherein the preparation for oral administration is a solid preparation.

(2-33) The preparation as described in the item (2-32), wherein the solid preparation is a tablet, a capsule or a granule.

(2-34) The preparation according to the item (2-33), wherein the solid preparation is a capsule.

(2-35) The preparation according to any one of (2-1) to (2-34), which contains the compound represented by the formula (I) or a salt thereof when converted into a free drug relative to the entire preparation 20 to 70% by weight.

(2-36) The pharmaceutical preparation according to the item (2-34), which contains the compound represented by the formula (I) or its salts 35 to 60% by weight.

(2-37) The preparation according to any one of (2-1) to (2-36), wherein each unit preparation, when converted into a free drug, contains the compound represented by formula (I) or its salt from 60 mg to 240mg.

(2-38) The preparation according to any one of (2-1) to (2-37), wherein each unit of preparation, when converted into a free drug, contains 140 mg to 140 mg of the compound represented by formula (I) or a salt thereof. 190mg.

(3-1) A method for producing a preparation with improved dissolution properties of the compound represented by the formula (I) or a salt thereof, characterized by (i) granulating granules containing the compound represented by the formula (I) or a salt thereof granules, (ii) disintegrating agents, and other additives are formulated as post-granulation additives.

(3-2) The method as described in item (3-1), wherein the aforementioned (ii) disintegrant is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, Sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(3-3) The method as described in the item (3-1) or (3-2), wherein the aforementioned (ii) disintegrant is when the sixteenth revision Japanese medicine is added per 1.0 g of the disintegrant. In the local dissolution test, when the first solution is 20 mL, its volume becomes more than 2.5 times the disintegrant.

(3-4) The method according to any one of (3-1) to (3-3), wherein the (ii) disintegrant is contained in an amount of 7.5 wt % or more and 30 wt % or less with respect to the entire formulation.

(3-5) The method according to any one of (3-1) to (3-4), wherein the average particle diameter of the particles is 150 μm or more and 1 mm or less.

(3-6) The method according to any one of (3-1) to (3-5), wherein the average particle diameter of the particles is 180 μm or more and 1 mm or less.

(3-7) The method according to any one of (3-1) to (3-6), wherein the particles have a bulk density of 0.5 g/mL or more and a tap density of 0.6 g/mL or more.

(3-8) The method according to any one of (3-1) to (3-7), wherein the granules of the aforementioned (i) contain a disintegrant in the granules.

(3-9) The method as described in item (3-8), wherein the disintegrant contained in the granules is selected from the group consisting of starch-sodium glycolate, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose Calcium, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

(3-10) The method according to any one of (3-8) or (3-9), wherein the disintegrating agent contained in the granules is the amount when the tenth disintegrant is added per 1.0 g of the disintegrating agent. Six revisions of the Japanese Pharmacopoeia Dissolution Test The volume of the first solution at 20 mL is 2.5 times or more of the disintegrant.

(3-11) The method as described in any one of (3-1) to (3-10), wherein the aforementioned particles contain a dissolution aid in the particles.

(3-12) The method as described in any one of (3-1) to (3-11), wherein the aforementioned dissolution aid is selected from the following group:

Citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyethylene (40) Stearic acid ester, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, aminoalkane methacrylate Ester copolymer E, seaweed Propylene Glycol, Casein, Sodium Caseinate, Carboxyvinyl Polymer, Carboxymethyl Ethyl Cellulose, Agar Powder, Guar Gum, Succinic Acid, Copovidone, Cellulose Acetate Phthalate, Tartaric Acid, Sulfonate Dioctyl Sodium Succinate, Zein, Skimmed Milk Powder, Sorbitan Trioleate, Lactic Acid, Aluminum Lactate, Palmitic-Ascorbic Acid, Hydroxyethyl Methyl Cellulose, Hydroxypropyl Methyl Cellulose Acetic Acid Ester succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene 35 castor oil, poly (sodium 4-styrene sulfonate), polyvinyl acetal Diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, laureth, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, dodecyl Sodium Benzene Sulfonate, Vinylpyrrolidone-Vinyl Acetate Copolymer, Sodium Lauryl Sarcosinate, Acetyltryptophan, Sodium Methyl Sulfate, Sodium Ethyl Sulfate, Sodium Butyl Sulfate, Sodium Octyl Sulfate , Sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate.

(3-13) The method according to any one of (3-1) to (3-12), wherein the dissolving aid is sodium lauryl sulfate obtained by crystallization.

(3-14) The method according to any one of (3-11) to (3-13), wherein the aforementioned dissolution aid is NIKKOL SLS.

(3-15) The method as described in any one of (3-11) to (3-14), wherein the weight ratio of the compound represented by the formula (I) to the dissolving aid is 100:2 to 100:60 .

(3-16) The method as described in any one of (3-1) to (3-15), wherein the aforementioned particles contain a binder in the particles.

(3-17) The method according to the item (3-16), wherein the binder is hydroxypropyl cellulose.

(3-18) The method according to any one of (3-1) to (3-17), which comprises the compound represented by the formula (I) or a salt thereof when converted into a free drug relative to the entire preparation 20 to 70% by weight.

(3-19) The method according to any one of (3-1) to (3-18), wherein each unit of the preparation, when converted into a free drug, contains 60 mg to 60 mg of the compound represented by formula (I) or a salt thereof. 240mg.

(3-20) The method according to any one of (3-1) to (3-19), wherein the preparation is the compound represented by the formula (I) 75 minutes after the start of the dissolution test at 37°C Preparations with a dissolution rate of 65% or more of its salts.

(3-21) A preparation produced by the method as described in any one of (3-1) to (3-20).

FIG. 1 is a graph showing the results of powder X-ray diffraction measurement of Type I crystals.

FIG. 2 is a graph showing the dissolution profiles of Examples 1 to 4 and 7 in the paddle method (100 revolutions per minute) of the Japanese Pharmacopoeia dissolution test.

FIG. 3 is a graph showing the dissolution profiles of Examples 1 and 4 to 7 in the stirring blade method (100 revolutions per minute) of the Japanese Pharmacopoeia dissolution test.

FIG. 4 is a graph showing the dissolution profiles of Examples 8 and 9 in the Japanese Pharmacopoeia dissolution test stirring blade method (100 revolutions per minute).

Fig. 5 is a graph showing the dissolution profiles of Examples 10 to 14 in the stirring blade method (100 revolutions per minute) of the dissolution test of the Japanese Pharmacopoeia.

Fig. 6-1 and Fig. 6-2 show stirring in the dissolution test of the Japanese Pharmacopoeia of Examples 10 and 15 to 20 (Fig. 6-1) and Examples 10 and 21 to 25 (Fig. 6-2). Graph of the dissolution profile in the leaf method (100 revolutions per minute).

Fig. 7 is a graph showing the dissolution profiles of Examples 26 and 27 in the Japanese Pharmacopoeia dissolution test stirring blade method (100 revolutions per minute).

FIG. 8 is a graph showing the dissolution profiles of Examples 28 and 29 in the Japanese Pharmacopoeia dissolution test stirring blade method (100 revolutions per minute).

In the present invention, "granule" refers to a raw material in the form of powder, block, solution, or molten liquid, etc., which is obtained by granulating a raw material such as a wet granulation method, a dry granulation method, or a heating granulation method. Particles of uniform shape and size. The machine used for granulation, from the viewpoint of dissolution, is preferable to a granulator with high-speed stirring rather than a mortar. Furthermore, the granules may also vary in size and shape during the formulation process (eg, the tableting step) used to obtain the formulation of the present invention.

The average particle size of the particles of the present invention is, for example, 150 μm or more, preferably 180 μm or more, more preferably 200 μm or more, still more preferably 250 μm or more, and even more preferably 300 μm or more. The upper limit of the average particle size of the particles is not particularly limited, for example, it is 1 mm.

The average particle size can be obtained by implementing the following steps: (i) After overlapping the sieves with different pore sizes (pore size: 850, 500, 355, 250, 180, 106, 75, 53, 0 μm), add sampling granulation (ii) shake the sieve for 3 minutes, (iii) measure the weight of the granulation remaining on each sieve, (iv) use the logarithmic normal distribution approximation from the aperture of each sieve and the accumulation rate of the undersize Calculate the particle size equivalent to 50% of the accumulation rate. When particles with a particle size exceeding 850 μm are present in 10% by weight or more, the particles corresponding to an accumulation rate of 50% are calculated using the Rosin-Rammler distribution from the pore size of each sieve and the accumulation rate of the oversized material. path.

The particles of the present invention preferably have a bulk density of 0.5g/mL or more and a tap density of 0.6g/mL or more; those with a bulk density of 0.6g/mL or more and a tap density of 0.7g/mL or more better. The upper limits of bulk density and tap density are not particularly limited, but 1.0 g/mL is preferred. Among them, the bulk density and tap density were measured according to the methods contained in the 16th revision of the Japanese Pharmacopoeia.

In the present invention, "wet granulation" refers to a method in which water or a mixed solution of water and alcohol is added as a solvent for granulation, and granulation is performed simultaneously with spraying or spreading to obtain powder.

The particle size can be adjusted by increasing or decreasing the amount of water or mixed liquid used in wet granulation.

The pharmaceutical composition or pharmaceutical preparation of the present invention contains (i) granules containing the compound represented by formula (I) or a salt thereof, and (ii) a disintegrant, and is a composition or preparation having excellent dissolution properties. (ii) Disintegrant means what is added as an additive after granulation. The "disintegrant" in the present invention refers to a component used to promote the rapid disintegration of the solid preparation after oral administration of the solid preparation. In the present invention, "additives after granulation" and "additive components after granulation" mean additives added to the outside of granulated particles. In addition to the disintegrant, additives such as lubricants and fluidizing agents may be optionally added to the additives.

The disintegrating agent in (ii) can include: starch-sodium glycolate, low-substituted hydroxyl Propyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carboxymethyl cellulose, etc., When adding 20 mL of the first solution of the dissolution test of the sixteenth revision of the Japanese Pharmacopoeia to every 1.0g of the disintegrant, the volume of the disintegrant is preferably 2.5 times or more, and it is better to be more than 5 times the disintegrant. . Preferable specific examples of the disintegrating agent include low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, and α-starch.

The usage amount of the disintegrant in (ii) is, for example, 5 wt % or more, preferably 7.5 wt % or more, more preferably 8.5 wt % or more, and 10 wt %, relative to the entire composition or formulation of the present invention. Excellent above. The upper limit of the usage amount is not particularly limited, for example, 30% by weight and 25% by weight. Furthermore, when the preparation of the present invention is a preparation having a film such as a capsule or a coated tablet, the above-mentioned usage amount means the amount of the total component covered by the film (the whole of the component filled in the capsule, the amount of the coating). the total amount of coated ingredients).

The particles (i) in the present invention may contain various additives in addition to the compound represented by the formula (I) or a salt thereof.

In one embodiment of the present invention, (i) granules contain the compound represented by formula (I) or a salt thereof, a disintegrating agent, a dissolving aid, an excipient and a binding agent. The granules may further contain one or more additives selected from lubricants, coating agents, stabilizers, flavors, and diluents.

The disintegrating agent contained in the granules of (i) in the present invention can be exemplified by: starch-sodium glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, α-starch, Sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carboxymethyl cellulose, etc. per 1.0g For the disintegrant, the disintegrant whose volume is 2.5 times or more when the first solution of the dissolution test of the 16th revision of the Japanese Pharmacopoeia is added is preferably more than 5 times. Preferable specific examples of the disintegrating agent include low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, and α-starch.

The "dissolution aid" contained in the particle (i) in the present invention means a surfactant, an organic polymer, or a pH adjuster.

"Surfactant" means a substance having both a hydrophilic group and a hydrophobic group in the molecule. In the surfactant, an ionic surfactant and a nonionic surfactant are included.

The ionic surfactant refers to an ionic surfactant that is freed as ions (charged atoms or atomic groups) when dissolved in water. Ionic surfactants are further classified into anionic surfactants, cationic surfactants and amphoteric surfactants according to the charge of the generated ions. In the present invention, nonionic surfactants and anionic surfactants are preferred.

Nonionic surfactants include: sorbitan fatty acid esters (C12 to 18), POE sorbitan fatty acid esters (C12 to 18), sugar ester surfactants such as sucrose fatty acid esters; POE Fatty acid ester types such as fatty acid esters (C12 to 18), POE resin esters, POE fatty acid diesters (C12 to 18); alcohol types such as POE alkyl ethers (C12 to 18); POE alkyl groups (C8 to 12) Phenyl ether, POE dialkyl (C8 to 12) phenyl ether, POE alkyl (C8 to 12) phenyl ether formaldehyde condensate and other alkylphenol type surfactants; polyoxyethylene-polyoxypropylene block polymerization compound, alkyl (C12 to 18) polyoxyethylene-polyoxypropylene Polyoxyethylene-polyoxypropylene block polymer type surfactants such as alkene block polymer ethers; POE alkylamine groups (C12 to 18), POE fatty acid amides (C12 to 18) and other alkylamine types; POE Bisphenol type surfactants such as fatty acid bisphenyl ether; POA benzyl phenyl (or phenyl phenyl) ether, POA styryl phenyl (or phenyl phenyl) ether and other polyaromatic ring type surfactants ; POE ether and ester polysiloxane and fluorine-based surfactants; POE castor oil, POE hydrogenated castor oil and other vegetable oil-based surfactants. Preferably, polyoxyethylene (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene 35 Castor oil, lauryl alcohol polyoxyethylene ether, etc.

Anionic surfactants include: alkyl sulfate (C12-18, Na, NH ₄ , alkanolamine), POE alkyl ether sulfate (C12-18, Na, NH ₄ , alkanolamine), POE Alkyl phenyl ether sulfate (C12 to 18, NH ₄ , alkanolamine, Ca), POE benzyl (or styryl) phenyl (or phenyl phenyl) ether sulfate (Na, NH ₄ , alkanolamine), polyoxyethylene, polyoxypropylene block polymer sulfate (Na, NH ₄ , alkanolamine) and other sulfate-type surfactants; paraffin (alkane) sulfonate (C12 to 22, Na, Ca, alkanolamine), AOS (C14 to 16, Na, alkanolamine), dialkylsulfosuccinate (C8 to 12, Na, Ca, Mg), alkylbenzenesulfonate (C12, Na , Ca, Mg, _NH4 , alkylamines, alkanols, amines, cyclohexylamines), mono- or dialkyl (C3 to 6) naphthalene sulfonates (Na, _NH4 , alkanolamines, Ca, Mg) , naphthalene sulfonate-formaldehyde condensate (Na, NH ₄ ), alkyl (C8 to 12) diphenyl ether disulfonate (Na, NH ₄ ), lignosulfonate (Na, Ca), POE Sulfonate surfactants such as alkyl (C8 to 12) phenyl ether sulfonate (Na), POE alkyl (C12 to 18) ether sulfosuccinic acid half ester (Na); fatty acid salts (C12 to 18 , Na, K, NH ₄ , alkanolamine), N-methyl-fatty acid sarcosinate (C12 to 18, Na), resinate (Na, K) and other carboxylic acid surfactants; POE alkyl (C12 to 18) ether phosphate (Na, alkanolamine), POE mono- or di-alkyl (C8 to 12) phenyl ether phosphate (Na, alkanolamine), POE benzyl (or styryl ) phenyl (or phenylphenyl) ether phosphate (Na, alkanolamine), polyoxyethylene-polyoxypropylene block polymer (Na, alkanolamine), phosphoester choline-phosphoester amide Phosphate surfactants such as ethanolimine (lecithin), alkyl (C8 to 12) phosphates, etc. Preferable examples include monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, dioctyl sodium sulfosuccinate, and lauryl sulfonate. Sodium sarcosinate, sodium dodecylbenzene sulfonate, etc.

Organic macromolecules refer to substances with a molecular weight of 10,000 or more mainly based on carbon. Organic polymers include proteins, polysaccharides, and synthetic resins derived from animals and plants.

Specific examples of organic polymers include: hydroxypropyl cellulose (hereinafter, also referred to as HPC), hydroxypropyl methyl cellulose, methyl cellulose, propylene glycol alginate, agar powder, guar gum, corn Polysaccharides such as protein and hydroxyethyl methyl cellulose, carboxyvinyl polymers, polyvinyl alcohol, or synthetic resins such as vinyl acetate resin, sodium polystyrene sulfonate, and phosphoproteins such as casein and sodium caseinate.

Among the organic polymers, those whose solubility in water is more than 1 g/100 g are called water-soluble polymers. Specifically: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone , hydroxyethyl Methyl cellulose, polyvinyl alcohol, etc.

Among the organic macromolecules, those that dissolve under the acidic conditions of gastric juice pH 1.2 to 3.5 are called gastric-soluble polymers, and those that dissolve rapidly at pH 6 to 8 in the intestine are called enteric-soluble polymers. Stomach-soluble polymers include aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like; enteric polymers include: methacrylic acid copolymer LD (emulsion turbid liquid), methacrylic acid copolymer S, purified shellac, carboxymethyl ethyl cellulose, cellulose acetate phthalate (cellacefate), hydroxypropyl methylcellulose acetate Succinate, casein, corn gluten, etc.

A pH adjuster refers to a substance that adjusts the pH of a solution by adding an acid or alkali agent to improve the solubility of poorly water-soluble or insoluble compounds. The pH adjuster can be appropriately selected according to the properties of the dissolved substances. For example, in the case of compounds that are poorly soluble or insoluble in alkaline water, the pH can be made acidic by adding an acid agent to improve the solubility.

Examples of pH adjusters include adipic acid, citric acid, trisodium citrate, gluconic acid, sodium gluconate, glucono-delta-lactone, potassium gluconate, succinic acid, monosodium succinate, and disodium succinate , Sodium acetate, L-tartaric acid, L-potassium hydrogen tartrate, L-sodium tartrate, DL-tartaric acid, DL-potassium hydrogen tartrate, DL-sodium tartrate, sodium bicarbonate, potassium carbonate (anhydrous), sodium carbonate, carbon dioxide, lactic acid , Sodium lactate, glacial acetic acid, disodium dihydrogen pyrophosphate, fumaric acid, monosodium fumarate, DL-malic acid, DL-sodium malate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, Dipotassium hydrogen phosphate, disodium hydrogen phosphate, etc.

And with adipic acid, citric acid, gluconic acid, glucono-delta-lactone, succinic acid, L-tartaric acid, DL-tartaric acid, carbon dioxide, lactic acid, glacial acetic acid, Acids such as fumaric acid, DL-malic acid and phosphoric acid are preferred.

In the present invention, the dissolution aid may be used in combination of two or more kinds in an appropriate ratio.

In the present invention, the dissolution aids are preferably those described below.

Citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyethylene (40) Stearic acid ester, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, aminoalkane methacrylate Ester copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, acetic acid phthalic acid Cellulose, tartaric acid, dioctyl sodium sulfosuccinate, corn gluten, skimmed milk powder, sorbitan trioleate, lactic acid, aluminum lactate, palmitic-ascorbic acid, hydroxyethylmethylcellulose, hydroxypropyl Methyl Cellulose Acetate Succinate, Polyoxyethylene (105) Polyoxypropylene (5) Diol, Polyoxyethylene Hydrogenated Castor Oil 60, Polyoxyethylene 35 Castor Oil, Sodium Poly(4-styrenesulfonate) ), polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauryl alcohol polyoxyethylene ether, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate , Sodium Dodecylbenzene Sulfonate, Vinylpyrrolidone-Vinyl Acetate Copolymer, Sodium Lauryl Sarcosinate, Acetyltryptophan, Sodium Methyl Sulfate, Sodium Ethyl Sulfate, Butyl Sulfate Sodium, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate.

In the present invention, the dissolution aid is more preferably the one described below.

Citric acid, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer LD, methyl cellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL - Malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethyl ethyl cellulose, succinic acid, copovidone, Dioctyl Sodium Sulfonate Succinate, Lactic Acid, Aluminum Lactate, Palmitic Acid-Ascorbic Acid, Hydroxyethyl Methyl Cellulose, Hydroxypropyl Methyl Cellulose Acetate Succinate, Polyoxyethylene Hydrogenated Castor Oil 60, Poly Oxyethylene 35 castor oil, poly (sodium 4-styrene sulfonate), polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, methacrylic acid copolymer S, laureth, sulfuric acid, Aluminum sulfate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, acetyltryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, octadecyl sulfate sodium

In the present invention, the dissolution aid is more preferably the one described below.

Citric acid, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer LD, methyl cellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL - Malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethyl cellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, Aluminum lactate, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, poly(sodium 4-styrene sulfonate), polyvinyl acetal diethyl amino acetate, methyl methacrylate Acrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinylpyrrolidone-vinyl acetate copolymer

The dissolving aid contained in the composition or preparation of the present invention is preferably 2% by weight to 60% by weight, more preferably 20% by weight to 60% by weight, relative to the compound represented by formula (I) (free drug). good.

In the present invention, when sodium lauryl sulfate is used, the crystal system is preferably obtained by crystallization rather than by spray drying. In addition, crystalline polymorphs of sodium lauryl sulfate are known as monohydrate, 1/2 hydrate, 1/8 hydrate, and unsolvated (document name: Journal of Crystal Growth 263 (2004) 480-490 ), any crystal can be used in the composition or preparation of the present invention.

The excipients arbitrarily included in the granules of (i) in the present invention can be, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partially alpha-formed starch, alpha-formed starch, pore starch, etc.; lactose Hydrate, fructose, glucose, mannitol, sorbitol and other sugars or sugar alcohols; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. Preferred excipients include starches such as starch, potato starch, corn starch, lactose hydrate, crystalline cellulose, anhydrous calcium hydrogen phosphate, etc., and lactose hydrate is more preferred. The usage amount of the excipient is preferably 5 to 60 parts by weight, more preferably 5 to 45 parts by weight, relative to 100 parts by weight of the composition or preparation.

Furthermore, when the preparation of the present invention is a preparation containing a film such as a capsule or a coated tablet, the above-mentioned usage amount refers to the whole of the components covered by the film (the whole of the components filled in the capsule, the whole of the components covered by the coating) the total amount of the covered ingredients).

Binders optionally included in the particles of (i) of the present invention As an agent, for example, hydroxypropyl cellulose, polyvinyl pyrrolidone, macrogol and the same compounds as the aforementioned excipients can be mentioned. Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, povidone (polyvinyl pyrrolidone), gum arabic powder, etc. Preferred can be hydroxypropyl cellulose. The usage amount of the binder is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, and even more preferably 0.5 to 10 parts by weight, relative to 100 parts by weight of the composition or preparation.

Furthermore, when the preparation of the present invention is a preparation containing a film such as a capsule or a coated tablet, the above-mentioned usage amount refers to the whole of the components covered by the film (the whole of the components filled in the capsule, the whole of the components covered by the coating) the total amount of the covered ingredients).

Preferred examples of lubricants optionally contained in the particles of (i) in the present invention include, for example: magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate Wait.

The stabilizer arbitrarily contained in the particles of (i) in the present invention can be, for example, parabens such as methylparaben and propylparaben; such as chlorobutanol, Alcohols such as benzyl alcohol and phenylethanol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

The flavor-correcting agents optionally included in the granules of the present invention include, for example, commonly used sweeteners, sour agents, and flavors.

The granules of (i) in the present invention are prepared by mixing the compound represented by formula (I) or its salt, and any disintegrating agent, dissolving aid, excipient. It is manufactured by granulating the composition of additives such as agents, lubricants, coating agents, binders, stabilizers, flavors, and diluents.

In the present invention, "pharmaceutical composition" means a mixture of two or more substances used for the treatment/prevention of diseases. In one embodiment of the present invention, the pharmaceutical composition can be used to manufacture pharmaceutical preparations.

In the present invention, "pharmaceutical preparation" means a preparation for the treatment/prevention of diseases or the like.

In the present invention, the "orally administered preparation" means a preparation that can be administered orally. By oral administration, it is meant that the formulation is swallowed into the gastrointestinal tract, where the active ingredient is primarily absorbed.

Formulations for oral administration specifically include solid formulations and liquid formulations such as lozenges, capsules, liquids, powders, troche, chewables, granules, gels, films, and sprays. As a liquid preparation, a suspension, a liquid preparation, a syrup, an elixir, etc. are mentioned, for example. Such preparations can be used as fillers in soft or hard capsules. Generally, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or appropriate oils, and one or more of them can be used. Emulsifying agent and/or suspending agent etc. as carrier. In addition, a liquid preparation can be prepared by dissolving, for example, the pharmaceutical composition of the present invention in a solid state in a carrier such as water.

In the present invention, "ALK" means "Anaplastic Lymphoma Kinase", that is, a receptor-type tyrosine kinase belonging to the insulin receptor family.

In the present invention, the salt of the compound represented by the formula (I) is preferably a hydrochloride, more preferably a monohydrochloride.

The compound represented by the formula (I) or its salt can be obtained from Patent Documents 2 to 4. Manufactured according to the method mentioned above.

In the present invention, the compound represented by the formula (I) or a salt thereof includes hydrates, various pharmaceutically acceptable solvates and crystalline polymorphs.

In one embodiment of the present invention, it is characterized by a hydrochloride of the compound represented by formula (I), which is in the powder X-ray diffraction pattern at 8.4°, 14.0°, 16.7°, 18.8°, 23.3° A crystal with a diffraction angle (2θ) of ° (hereinafter, referred to as I-type crystal) has a peak.

Type I crystals can be obtained by dropping the compound represented by formula (I) into the mixed solution of ethanol and hydrochloric acid (compared to the compound of formula (1), containing 1 Molar equivalent or more hydrochloric acid) to obtain.

One of the measurement results of the powder X-ray diffraction of the I-type crystal is shown in Fig. 1, and one of the peaks in the powder X-ray diffraction pattern is shown below, for example.

[Table 1]

In the present invention, the analysis by powder X-ray diffraction can be performed in accordance with a general method such as "powder X-ray diffraction measurement" described in the Japanese Pharmacopoeia (15th revision). In addition, it is recorded in the Japanese Pharmacopoeia that for the same crystal form, the diffraction angle 2θ is usually within the range of ±0.2 degrees. Consistent. Therefore, not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction are completely consistent, but also crystals in which the diffraction angles of the peaks are consistent with an error of about ±0.2 degrees are included in the present invention.

An example of the measurement conditions of powder X-ray diffraction analysis can be as follows:

Measuring device: X'Pert-Pro MPD (manufactured by PANalytical)

Opposite cathode: Cu

Tube voltage: 45kV

Tube current: 40mA

Step size: 0.017

Scan axis: 2θ

Sampling time for each step: 43 seconds

Scanning range: 3 to 40°

The pharmaceutical composition and pharmaceutical preparation of the present invention contain (i) granules containing the compound represented by formula (I) or a salt thereof, and (ii) a disintegrant, and are compositions or preparations excellent in dissolution properties.

In the present invention, "a composition or preparation with excellent dissolution properties" and "a preparation with improved dissolution properties", for example, a composition or preparation with a drug dissolution rate of 65% or more after the initiation of the dissolution test at 37°C for 75 minutes, preferably Compositions or preparations with a drug dissolution rate of 70% or more after 75 minutes from the start of the dissolution test at 37°C, more preferably, a drug dissolution rate of 40% or more after 30 minutes from the start of the dissolution test at 37°C and 75 minutes after the start of the drug dissolution rate The composition or preparation with a rate of 65% or more, especially the composition with a drug dissolution rate of 40% or more after 30 minutes from the start of the dissolution test at 37°C and a drug dissolution rate of 70% or more after 75 minutes substance or preparation. In the aforementioned dissolution test, the test solution used 900mL of the first solution of the sixteenth revision of the Japanese Pharmacopoeia containing 4% polyoxyethylene (10) octyl phenyl ether. The stirring blade method was tested, and the test was carried out at 100 revolutions per minute.

The preparation of the present invention can be produced by a generally used production method after mixing the granules of (i) in the present invention together with a disintegrant and optional additives. Preferably, it is manufactured according to the following manufacturing method.

1) After mixing the compound represented by the formula (I) with additives such as disintegrants, dissolving aids, excipients, and adhesives, add or spray a solvent (such as purified water, ethanol, or its mixture) etc.) while granulating. To the obtained granules (granules), the disintegrant of (ii), any appropriate amount of lubricants, fluidizers and other additives are added and mixed, and then filled in capsules, or compression-molded, etc., to manufacture the present invention. preparations.

2) After mixing the compound represented by formula (I) with additives such as disintegrants, dissolving aids, excipients, etc., add or spray to disperse or dissolve the binder and other additives as needed in a solvent (such as The solution obtained in purified water, ethanol, or a mixture thereof, etc.) is granulated. To the obtained granules (granules), the disintegrant of (ii), any appropriate amount of lubricants, fluidizers and other additives are added and mixed, and then filled in capsules, or compression-molded, etc., to manufacture the present invention. preparations.

In the methods of 1) and 2) above, granules granulated by a dry granulation method, a heating granulation method, or the like instead of the wet granulation method can also be used.

The composition and preparation of the present invention may contain, in addition to (ii) a disintegrant, a lubricant or a fluidizer as an additive after granulation. lubricating Examples of the agent and fluidizing agent include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate, and preferably, magnesium stearate. The usage amount of the lubricant and fluidizing agent is preferably 0.01 to 20 parts by weight, more preferably 0.05 to 15 parts by weight, relative to 100 parts by weight of the composition or preparation. Furthermore, when the preparation of the present invention is a preparation containing a film such as a capsule and a coated tablet, the above-mentioned usage amount refers to the whole of the components covered by the film (the whole of the components filled in the capsule, the coating the total amount of coated ingredients).

Dragee-coated or film-coated lozenges can be obtained from lozenges, further using suitable coatings.

As a sugar-coating base, for example, sugars such as white sugar and butane erythritol, or sugar alcohols can be used, and can also be used in combination with talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, and carnauba wax. One or more of the same.

As a coating agent, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin, etc. are mentioned, for example.

Enteric film coating base, for example: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, o-acetic acid Cellulose-based polymers such as cellulose phthalate; methacrylic acid copolymer L [EUDRAGIT L (trade name), Evonik Degussa Corporation], methacrylic acid copolymer LD [EUDRAGIT L-30D55 (trade name), Evonik Degussa Corporation] ], methacrylic acid copolymer S [EUDRAGIT S (trade name), Evonik Degussa company] and other acrylic polymers; natural products such as shellac.

Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; amino alkyl methacrylate copolymer RS [EUDRAGIT RS (trade name), Evonik Degussa Corporation], ethyl acrylate - Acrylic polymers such as methyl methacrylate copolymer suspension [EUDRAGIT NE (trade name), Evonik Degussa Corporation]; cellulose acetate, etc.

The above-mentioned coating bases can also be used by mixing two or more kinds thereof in an appropriate ratio.

In the coating agent, water-soluble substances, plasticizers, etc. for adjusting the dissolution rate may be added as needed. Water-soluble substances can be selected from water-soluble polymers such as hydroxypropyl methylcellulose, sugar alcohols such as mannitol, sugars such as white sugar and anhydrous maltose, sucrose fatty acid esters and polyoxyethylene polyoxypropylene One or more of surfactants such as alcohol, polysorbate, and sodium lauryl sulfate. Plasticizer, can be used selected from: acetylated monoglyceride, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain fatty acid triglyceride, lemon One or more of acetyl triethyl acid, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleyl alcohol, etc.

Furthermore, as the method for coating the tablet with the aforementioned coating layer, a general method can be used, for example, pan coating, flow coating, rolling coating, and rolling rolling coating. Law. Furthermore, the coating liquid used in such a method can be obtained by mixing the aforementioned coating base, the aforementioned talc, and a solvent (preferably ethanol or a mixture of ethanol and water). Then, the solid content concentration of such a coating liquid is preferably in the range of 5 to 15 mass % with respect to the mass of the entire coating liquid.

The compound represented by formula (I) or a salt thereof has excellent ALK inhibitory effect and good in vivo stability, and can be used as a prophylactic or therapeutic agent (especially a therapeutic agent) for proliferative diseases. In addition, the compound represented by the formula (I) or a salt thereof can be used as leukemia (acute skeletal leukemia, chronic skeletal leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's lymphoma, etc.) , non-Hodgkin's lymphoma, etc.), brain tumors, neuroblastoma tumors, glial tumors, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, colorectal cancer, Breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, pelvic and ureteral cancer, bladder cancer, ovarian cancer, uterine cancer, testicular cancer, prostate cancer, etc. A prophylactic or therapeutic agent (especially a therapeutic agent) for the disease. Furthermore, the compound of the present invention or a salt thereof can be used as a preventive or therapeutic agent (especially, a therapeutic agent) for the invasion/metastasis of solid cancer. In addition, it is also effective as a preventive or therapeutic agent for other diseases related to ALK, such as depression or cognitive dysfunction.

When the composition of the present invention is used as an ALK inhibitor, a therapeutic or preventive agent for proliferative diseases, or a therapeutic or preventive agent for depression or cognitive dysfunction, the administration method thereof includes oral, rectal , parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (infusion, powder, ointment, gel or cream) administration and inhalation (oral intranasal or nasal spray) etc. The form of its administration includes, for example: lozenges, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, as well as filling into suitable subdivided Parenteral solutions in containers for each dose. In addition, the administration form can be adapted to various administration methods including the adjusted release formulation such as subcutaneous implantation.

Oral administration is preferably in the form of tablets, capsules, granules or powders.

When the composition or preparation of the present invention is used as an ALK inhibitor, a therapeutic or preventive agent for proliferative diseases, or a therapeutic or preventive agent for depression or cognitive dysfunction, the active ingredient (represented by the formula (I) The dosage of the compound of the present invention or its salt) varies depending on symptoms, age, body weight, relative health status, the presence of other drugs, the method of administration, and the like. For example, for patients (warm-blooded animals, especially humans), the generally effective amount, in terms of the active ingredient (the compound of the present invention represented by formula (I) or a salt thereof), when it is an oral agent, is 1 kg per day. The body weight is preferably 0.001 to 1000 mg, preferably 0.01 to 300 mg per 1 kg of body weight. The daily dose is preferably in the range of 1 to 1500 mg for adult patients of normal weight. When it is a parenteral preparation, it is preferably 0.001 to 1000 mg per 1 kg of body weight per day, and more preferably 0.01 to 300 mg per 1 kg of body weight. It is better to administer it once a day or several times, depending on the symptoms.

The composition of the present invention contains, for example, 20 to 70 wt %, more preferably 30 to 60 wt %, and 35 Even more preferably, to 60% by weight.

In the preparation of the present invention, the compound represented by the formula (I) or its salt is converted into a free drug, for example, 20 to 70 wt %, more preferably 30 to 60 wt %, preferably 35 to 60 wt %, relative to the entire preparation. % by weight is even better. In addition, when the preparation of the present invention is a preparation containing a film such as a capsule or a coated tablet, the above-mentioned content means relative to the whole of the components covered by the film (filling The content of the whole of the ingredients to be filled in the capsule, the whole of the ingredients to be covered by the coating). That is, when the preparation of the present invention is a capsule, the compound represented by the formula (I) or a salt thereof is converted into a free drug, for example, 20 to 70% by weight relative to the whole of the components filled in the capsule. 30 to 60% by weight is more preferable, and 35 to 60% by weight is even more preferable.

Preferably, the preparation of the present invention is that, per unit preparation, the compound represented by formula (I) or its salt is converted into a free drug, for example, 60 to 240 mg, more preferably 100 to 200 mg, 140 to 190 mg and more good.

According to other embodiments of the present invention, the following inventions (4-1) to (4-7) are provided.

(4-1)

A preparation, which is a pharmaceutical preparation containing a poorly water-soluble or insoluble compound and sodium lauryl sulfate, wherein the aforementioned sodium lauryl sulfate is obtained by crystallization.

(4-2)

The preparation as described in item (4-1), wherein sodium lauryl sulfate is a 1/8 hydrate crystal.

(4-3)

A method for producing a pharmaceutical preparation with improved dissolution properties of poorly water-soluble or insoluble compounds, comprising mixing crystallized sodium lauryl sulfate and any other additives into the aforementioned compound.

(4-4)

A kind of manufacturing method of the pharmaceutical preparation that improves the dissolution property of water-insoluble or insoluble compound, it is to prepare sodium lauryl sulfate in the aforementioned compound of NIKKOL SLS, and any other additives.

(4-5)

A method for improving the dissolution property of the compound, which is a method for improving the dissolution property of the compound for a pharmaceutical preparation containing a poorly water-soluble or insoluble compound, which is to formulate sodium lauryl sulfate obtained by crystallization in the aforementioned compound, and any other additives.

(4-6)

A method for improving the dissolution property of a pharmaceutical preparation containing a poorly water-soluble or insoluble compound is to prepare NIKKOL SLS of sodium lauryl sulfate and any other additives in the aforementioned compound.

(4-7)

The method as described in any one of (4-3) to (4-6), wherein the sodium lauryl sulfate is a 1/8 hydrate crystal.

In the inventions of (4-1) to (4-7), "insoluble or insoluble in water" means that the solubility in water at 25°C is less than 100 μg/mL. In one embodiment of the present invention, "poorly water-soluble or insoluble" means that the solubility in water at 25°C is less than 10 μg/mL. The solubility can be measured according to the usual method. Examples of poorly water-soluble or insoluble compounds include 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-side oxy-6 , 11-Dihydro-5H-benzo[b]carbazole-3-carbonitrile and its salts.

In the inventions of (4-1) to (4-7), "crystallization" refers to crystals of sodium lauryl sulfate precipitated from a solution or suspension containing sodium lauryl sulfate.

In the inventions of (4-1) to (4-7), the term "improved dissolution "Pharmaceutical preparation with improved dissolution properties", for example, the drug dissolution rate after 75 minutes from the start of the dissolution test at 37°C is 65% or more, preferably the drug dissolution rate after 75 minutes from the start of the dissolution test at 37°C. 70% or more, and preparations with such a dissolution profile. In the aforementioned dissolution test, 900 mL of the first solution of the 16th revised Japanese Pharmacopoeia dissolution test containing polyoxyethylene (10) octyl phenyl ether 4% in the test solution was used, according to the 16th revised Japanese medicine. The local dissolution test was carried out by stirring blade method at 100 revolutions per minute.

The meaning of the term "pharmaceutical preparation" in the items (4-1) to (4-7) is as described above.

The formulations described in the items (4-1) to (4-7) use a poorly water-soluble or insoluble compound, sodium lauryl sulfate, and optional excipients, disintegrants, binders, lubricants, and coatings Additives such as stimulants, stabilizers, flavors, and diluents are produced by generally known methods. In addition, it can also be manufactured according to the method described in the specification of this application.

The above-mentioned excipients include, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partially α-starch, α-starch, and pore starch; lactose hydrate, fructose, glucose, mannitol, sorbitan Sugars or sugar alcohols such as sugar alcohols; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. The aforementioned disintegrants include, for example: the same compounds as the aforementioned excipients and chemically modified starch/cellulose such as croscarmellose sodium, starch-sodium glycolate, and crospovidone kind. Specific examples of disintegrating agents include, for example, starch-sodium glycolate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, and crospovidone. , Low-substituted hydroxypropyl cellulose, hydroxypropyl starch, etc. aforementioned Examples of the binder include polyvinylpyrrolidone, polyethylene glycol, and the same compounds as the aforementioned excipients. Specific examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), acacia powder, and the like. As said lubricant, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc. are mentioned, for example.

Crystal polymorphs of sodium lauryl sulfate, known as monohydrate, 1/2 hydrate, 1/8 hydrate, and unsolvate (document name: Journal of Crystal Growth 263 (2004) 480-490), Any of the crystals can be used in the inventions (4-1) to (4-7).

(Example)

The following examples are given to illustrate the present invention in more detail, but the present invention is not limited thereto. In addition, in Examples 1-27, the sodium lauryl sulfate type|system|group used NIKKOL SLS (trade name, Nikko Chemical).

Embodiments 1 to 7: the relationship between the addition of SLS and the formulation amount and the solubility of the original drug

(1) Manufacture of preparations

According to the amount of each component described in Table 2, preparations of 6 kinds of formulations in which the amount of sodium lauryl sulfate (SLS) was changed were prepared. The formulation components of the granules are respectively added to a high-speed stirring granulator for pre-mixing, sprayed with an appropriate amount of purified water, stirred and granulated, and then vacuum-dried to obtain dry powder. The dried powder was classified into particle size with a classifier, and the obtained particle size classified powder and the additives after granulation (calcium carboxymethyl cellulose, magnesium stearate) were mixed with a mixer to prepare a formulated powder. Capsules are filled with the prepared powder to produce capsules agent.

[Table 2]

(2) Preparation evaluation and results

For Examples 1 to 4 and 7, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 5% of polyoxyethylene (10) octyl phenyl ether in the test solution was used in the Japanese Pharmacopoeia dissolution test stirring blade method. , the dissolution profile of the test at 37°C at 100 rpm is shown in Figure 2. For Examples 1 and 4 to 7, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 4% of polyoxyethylene (10) octyl phenyl ether in the test solution was used, and the Japanese Pharmacopoeia dissolution test stirring blade method was used. , the dissolution profile of the test at 37°C at 100 rpm is shown in Figure 3.

(3) Conclusion

As shown in the dissolution profiles of Figures 2 and 3, all of Examples 1 to 6 with SLS improved dissolution relative to Example 7 without SLS in the formulation. Specifically, it was shown that the greater the amount of SLS in the formulation, the more the tendency to improve the dissolution. In particular, from the comparison of Examples 6 and 7 in Fig. 3, it was confirmed that even if a small amount of SLS was included in the formulation, the dissolution was significantly improved. sex.

Examples 8 and 9: Relationship between particle size of particles and solubility of the original drug

(1) Manufacture of preparations

According to the amount of each component described in Table 3, the amount of purified water was adjusted, and preparations of two formulations having different particle diameters were prepared. The formulation components of the granules were respectively added to a high-speed stirring granulator for pre-mixing, sprayed with the purified water shown in Table 2, stirred and granulated, and then vacuum-dried to obtain dry powder. The dried powder was classified into particle size with a classifier, and the obtained particle size classified powder and the additives after granulation (calcium carboxymethyl cellulose, magnesium stearate) were mixed with a mixer to prepare a formulated powder. Capsules were filled with this preparation powder, and capsules were produced.

[table 3]

(2) Preparation evaluation and results

When the particle size distribution of the particle size classified powder was measured, the average particle size of Example 8 was 172 μm and that of Example 9 was 300 μm. For Examples 8 and 9, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 5% of polyoxyethylene (10) octyl phenyl ether in the test solution was used in the Japanese Pharmacopoeia dissolution test stirring blade method. The dissolution profile of the test at 100 revolutions per minute at 37°C is shown in Figure 4.

Furthermore, the average particle size is from the overlapping of sieves with different apertures (pore size: 850, 500, 355, 250, 180, 106, 75, 53, 0 μm), add 6 g of sampled granules, and shake for 3 Minutes later, the weight of the granulated material remaining on each sieve was measured, and the particle size equivalent to 50% of the accumulation rate was calculated by using the approximate value of the logarithmic normal distribution from the aperture of each sieve and the accumulation rate of the undersize.

(3) Conclusion

As shown in Fig. 4, Example 9 with a large particle size showed improved dissolution properties.

It has been reported that the dissolution properties are reduced when the particle size is large (Yuko Ohno, "Pharmaceutical studies related to the manufacturing parameters of the granulation step affecting the dissolution characteristics of pharmaceutical products", http://mitizane.11.chiba-u.jp /metadb/up/irwg10/IY-K-Y-049.pdf, International Journal of Pharmaceutics 338 (2007) 79-86). Therefore, the dissolution of formulations containing large particle size particles can be improved, which is completely unexpected.

Embodiments 10 to 14: the addition method of disintegrant and the relationship between the addition amount and the solubility of the original drug

(1) Manufacture of preparations

Five formulations were prepared by changing the amount of calcium carboxymethyl cellulose added to the additive components after granulation according to the amounts of the components described in Table 4. The formulation components of the granules are respectively added to a high-speed stirring granulator for pre-mixing, sprayed with an appropriate amount of purified water, stirred and granulated, and then vacuum-dried to obtain dry powder. The dry powder was subjected to particle size classification with a classifier, and the obtained particle size classified powder and the additive component (calcium carboxymethyl cellulose) after granulation were mixed to prepare a formulated powder. Capsules were filled with this preparation powder, and capsules were produced.

[Table 4]

(2) Preparation evaluation and results

For Examples 10 to 14, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 7% of polyoxyethylene (10) octyl phenyl ether in the test solution was used in the Japanese Pharmacopoeia dissolution test stirring blade method. The dissolution profile of the test at 37°C at 100 revolutions per minute is shown in Figure 5.

(3) Conclusion

As shown in Fig. 5, when comparing the formulations with the post-granulation additives, when the post-granulation additives were added in an amount of 3 to 5% by weight, it was confirmed that the elution was slightly improved compared to when the post-granulation additives were not added. At 10% by weight or more, it was confirmed that the dissolution property was significantly improved.

Examples 15 to 25: Specifics containing calcium carboxymethyl cellulose The relationship between the disintegrant and the solubility of the original drug

(1) Manufacture of preparations

To the granules prepared in Example 10, the post-granulation additive components described in Table 5 (11 types in total, Examples 15 to 25) were added and mixed to obtain a prepared powder. The compounding ratio is based on the proportion of the granules obtained in Example 10 being 9 parts by weight and the additives after granulation being 1 part by weight. Capsules were filled with this preparation powder, and capsules were produced.

[table 5]

(2) Preparation evaluation and results

For Examples 10 and 15 to 25, polyoxygen in the test solution will be used The first solution of the dissolution test of ethylene (10) octyl phenyl ether 7% of the Japanese Pharmacopoeia 900mL, the dissolution curve of the Japanese Pharmacopoeia dissolution test stirring blade method at 37 ° C at 100 revolutions per minute is shown in Figures 6-1 and 6-2.

(3) Conclusion

As shown in Figure 6, the disintegrants with high dissolvability are low-substituted hydroxypropyl cellulose (Example 16), calcium carboxymethyl cellulose (Example 17), sodium bicarbonate (Example 18), Alpha-starch (Example 19).

When 20 mL of the first solution of the dissolution test of the Japanese Pharmacopoeia was added per 1.0 g of the disintegrant, it was confirmed that the volume of low-substituted hydroxypropyl cellulose and carboxymethyl cellulose calcium increased by 5 times or more, and the cross-linked carboxymethyl cellulose The volume of sodium cellulose, sodium starch glycolate, and α-starch is 2.5 times or more.

Examples 26 and 27: Comparison of disintegrants

(1) Manufacture of preparations

Using low-substituted hydroxypropyl cellulose and calcium carboxymethyl cellulose as disintegrants, two formulations of different types of disintegrants were prepared in accordance with the amounts of the components described in Table 6. The formulation components of the granules are respectively added to a high-speed stirring granulator for pre-mixing, sprayed with an appropriate amount of purified water, stirred and granulated, and then vacuum-dried to obtain dry powder. The dry powder is subjected to particle size classification with a classifier, and the obtained particle size classified powder and the additives after granulation are mixed with a mixer to prepare a formulated powder. Capsules were filled with this preparation powder, and capsules were produced. In addition, Example 26 is the same prescription ingredient as Example 1.

[Table 6]

(2) Preparation evaluation and results

For Examples 26 and 27, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 5% of polyoxyethylene (10) octyl phenyl ether in the test solution was used in the Japanese Pharmacopoeia dissolution test stirring blade method. The dissolution profile when tested at 37°C at 100 revolutions per minute is shown in Figure 7.

As shown in Figure 7, the disintegrants are low-substituted hydroxypropyl cellulose and carboxymethyl cellulose calcium, both of which show excellent dissolution properties. In addition to the differences, the carboxymethyl cellulose calcium shows another better.

Examples 28 and 29: Comparison of various sodium lauryl sulfate commercial products

(1) Manufacture of preparations

Using different commercial products as sodium lauryl sulfate, and in accordance with the amounts of the components described in Table 7, two kinds of formulations were prepared. The formulation components of the granules are respectively added to a high-speed stirring granulator for pre-mixing, sprayed with an appropriate amount of purified water, stirred and granulated, and then vacuum-dried to obtain dry powder. The dry powder is classified by particle size classification machine, and the obtained particle size classified powder and the additive components after granulation are mixed with a mixer to prepare a formulated powder. Capsules were filled with this preparation powder, and capsules were produced. Furthermore, the crystal form of the sodium lauryl sulfate used in these examples was confirmed to be 1/8 hydrate as a result of powder X-ray diffraction analysis.

[Table 7]

(2) Preparation evaluation and results

For Examples 28 and 29, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test containing 4% of polyoxyethylene (10) octyl phenyl ether in the test solution was used in the Japanese Pharmacopoeia dissolution test stirring blade method. The dissolution profile when tested at 37°C at 100 revolutions per minute is shown in Figure 8.

As shown in Figure 8, the formulation using NIKKOL SLS (Nikko Chemical) showed unexpectedly high dissolution compared to the formulation using sodium lauryl sulfate obtained from Kolliphor ^® SLS FINE (BASF).

The properties of the sodium lauryl sulfate used in these examples were observed with an optical microscope, etc. It was found that NIKKOL SLS (Nikko Chemical) was obtained by crystallization, and Kolliphor ^® SLS FINE (BASF) was obtained by spray drying. Therefore, it was found that the preparation method of sodium lauryl sulfate affects the dissolution properties of the preparation.

Example 30: Determination of Bulk Density and Tap Density of Particles

The bulk density and tap density of the granules in the formulations of Examples 1 to 9, 26 and 27 were determined by the 2nd method of the Japanese Pharmacopoeia of the 16th revision. The results are shown in Table 8.

[Table 8]

Reference Example 1: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxy-6,11-dihydro- Form I crystal of one of 5H-benzo[b]carbazole-3-carbonitrile hydrochloride

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxy-6,11-dihydro 400 g of -5H-benzo[b]carbazole-3-carbonitrile was dissolved in a mixed solvent of 4.8 L of methyl ethyl ketone, 1.44 L of acetic acid and 1.68 L of distilled water, and the solution was added dropwise to 12 L of ethanol and 2 N of ethanol at 60°C 0.8L of hydrochloric acid in the mixture. The precipitated solid was collected by filtration, washed with 2 L of ethanol, and dried to obtain 357 g of type I crystals of hydrochloride, one of the title compounds.

Reference Example 2: Powder X-ray Diffraction Analysis

For 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxy-6,11-dihydro-5H-benzene The powder X-ray diffraction of the type I crystal of [b]carbazole-3-carbonitrile monohydrochloride was measured under the following conditions. The measurement results of the type I crystals are shown in FIG. 1 .

Measuring device: X'Pert-Pro MPD (manufactured by PANalytical)

Opposite cathode: Cu

Tube voltage: 45kV

Tube current: 40mA

Step size: 0.017

Scan axis: 2θ

Sampling time for each step: 43 seconds

Scanning range: 3 to 40°

The pattern in this case is experimental data, not a representative diagram of this case, so there is no designated representative diagram.

Claims (17)

A preparation comprising (i) particles comprising a compound represented by formula (I) or a salt thereof; wherein the average particle diameter of the aforementioned particles is 180 μm or more, the bulk density is 0.5 g/mL or more, and the tap density is 0.6 g /mL or more;

The preparation according to claim 1, wherein the bulk density of the particles is 0.6 g/mL or more, and the tap density is 0.7 g/mL or more. The preparation according to item 1 or 2 of the claimed scope, wherein the upper limit of the bulk density and tap density of the aforementioned particles is 1.0 g/mL. The preparation according to claim 1 or 2, wherein the average particle diameter of the aforementioned particles is 200 μm or more. The preparation according to item 1 or 2 of the claimed scope, wherein the upper limit of the average particle size of the aforementioned particles is 1 mm. The preparation as described in item 1 or 2 of the claimed scope further contains (ii) a disintegrant. The preparation described in claim 6 of the claimed scope contains 5% by weight or more of the above-mentioned (ii) disintegrant. The preparation described in claim 6 of the claimed scope contains 7.5% by weight or more of the above-mentioned (ii) disintegrant. The preparation according to item 6 of the claimed scope, wherein the aforementioned (ii) disintegrant is selected from the group consisting of: starch-sodium glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, α starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose. The preparation according to claim 1 or 2, wherein the aforementioned granules contain a disintegrant in the granules. The preparation according to item 10 of the scope of the application, wherein the disintegrant contained in the granules is selected from the group consisting of: starch-sodium glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and sodium bicarbonate , Alpha starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose. The preparation according to claim 1 or 2, wherein the aforementioned granules contain a dissolution aid in the granules. The preparation according to item 12 of the claimed scope, wherein the aforementioned dissolution aid is sodium lauryl sulfate. The preparation according to claim 1 or 2, wherein the aforementioned granules contain a binder within the granules. The preparation according to claim 14, wherein the aforementioned binder is hydroxypropyl cellulose. The preparation according to item 1 or 2 of the claimed scope of application, wherein each unit preparation contains 60 mg to 240 mg of the compound represented by formula (I) or its salt when converted into a free drug. The preparation as described in item 1 or 2 of the claimed scope, wherein each unit system The dose contains 140 mg to 190 mg of the compound represented by the formula (I) or a salt thereof when converted into a free drug.

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